PDGF-C and -D are the major isoforms expressed in human retinal pigment epithelium (RPE). Functionally active PDGFR-&#945; and -&#946; are mainly expressed at the apical membrane. PDGF-BB, -CC, -DD significantly increased proliferation while PDGF-BB, -AB and -DD significantly increased cell migration, suggesting a critical role in RPE pathophysiology. A pro-inflammatory cytokine mixture (TNF&#945;/IL-1&#946;/IFN&#947;) abrogated PDGF-induced proliferation and migration by inducing apoptosis, and by disrupting the cytoskeleton and tight junctions. [unreadable] [unreadable] Interferon gamma (IFNg) is one of the most important inflammatory mediators which are up-regulated in many retinal diseases. These sight threatening retinal diseases occur in the back of the eye; they mainly affect photoreceptors and the closely adjacent retinal pigment epithelial cells, which serve to protect the health and integrity of the neural retina. Functionally active IFNg receptor is mainly localized at the basolateral membrane of human fetal retinal pigment epithelium (hfRPE). The activation of this receptor significantly inhibits basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and epidermal growth factor (EGF) induced RPE migration and proliferation. In contrast, type I IFN (IFN alpha and IFN beta) did not affect RPE proliferation. The inhibitory effects of IFNg on hfRPE were significantly blocked by JAK inhibitor I and by AG490 , but not by JAK3 inhibitor. In addition, activation of this JAK/STAT pathway up-regulates interferon regulatory factor 1 (IRF-1), but has no effect on IRF-2 and ICSBP/IRF-8. Interestingly, IFNg significantly stimulated the proliferation of cells from adjacent choroidal tissue. Addition of IFNg to the basal, but not the apical bath, significantly increased fluid transport (JV) across hfRPE monolayer. The IFNg induced JV increase was significantly blocked by a specific inhibitor of the cystic fibrosis transmembrane conductance regulator (CFTR) (CFTRinh-172). CFTR protein is expressed and mainly localized on the basolateral membrane of hfRPE. IFNg induced JV increase was blocked by pretreatment with cyclohexamide (4 or 24 hours). IFNg had no measurable effects on intracellular cAMP or Ca2+ levels. IFNg did however increase the phosphorylation of P38 MAPK. In addition, the IFNg induced JV increase was significantly reduced by the addition of P38 MAPK inhibitors, SB203580 and SB202190. A further JV decrease was produced by the subsequent addition of CFTRinh-172. Although IFNg has no measurable effect on intracellular cAMP, IFNg stimulated Jv increase was significantly inhibited by specific protein kinase A (PKA) inhibitor (H-89) and Rp-8-Br-cAMPS, which competitive blocked cAMP binding to PKA and blocked the effect of cAMP. We conclude that IFNg inhibits RPE migration and proliferation, activates CFTR-dependent fluid absorption across RPE in vitro and in vivo, and that JAK/STAT1, IRF-1, P38 MAPK and PKA are all involved in mediating these responses. These finding suggest several therapeutic targets for treating proliferative retinal diseases and removing the fluid accumulation in the subretinal space that occurs following many retinal pathologies.